Tryptase inhibitors

ABSTRACT

Compounds of the formula I, in which M, A1, A2, K1 and K2 have the meanings given in the description are novel effective tryptase inhibitors.

APPLICATION OF THE INVENTION

[0001] The invention relates to novel tryptase inhibitors which are usedIn the pharmaceutical industry for preparing medicaments.

KNOWN TECHNICAL BACKGROUND

[0002] The international applications WO95/32945 (=U.S. Pat. No.5,656,660), WO96/09297 (=U.S. Pat. No. 6,022,969, U.S. Pat. No.6,221,228), WO98/04537, WO99/12918, WO99/24395, WO99/24407, WO99/40073,WO99/40083 and WO00/14097 describe low-molecular-weight bivalentcompounds for use as tryptase inhibitors.

DESCRIPTION OF THE INVENTION

[0003] It has now been found that the compounds of the formula I, whichare described In more detail below, have surprising and particularlyadvantageous properties.

[0004] The invention provides compounds of the formula I

[0005] in which

[0006] M is a central building block selected from the group below

[0007] where

[0008] R1 is carboxyl, 1-4C-alkoxycarbonyl or hydroxy-1-4C-alkyl,

[0009] R2 Is selected from the group consisting of

[0010] in which R21 is 1-4C-alkyl,

[0011] R3 is hydrogen, 1-4C-alkyl or 1-4C-alkylcarbonyl,

[0012] D1 is a bond or —CH₂—O—,

[0013] D2 is a bond or —O—CH₂— and

[0014] n is 1 or 2,

[0015] A1 is —O—B1-A3-, -A5-B1-O—, —C(O)—, —C(O)NH—, —NH—C(O)—,—O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0016] A2 is —O—B2-A4-, -A6-B2-O—, —C(O)—, —C(O)—NH—, —NH—(O)—,—O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0017] A3 and A4 are identical or different and are —C(O)—, —C(O)—NH—,—NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0018] A5 and A6 are identical or different and are —C(O)—, —C(O)—NH—,—NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0019] B1 and B2 are identical or different and are 1-4C-alkylene,

[0020] K1 is —B3-X1, —B3-Y1 or —B3-Z1-B5-X1,

[0021] K2 is —B4-X2, —B4-Y2 or —B4-Z2-B6-X2,

[0022] B3 and B4 are identical or different and are a bond or1-4C-alkylene,

[0023] B5 and B6 are identical or different and are a bond or1-2C-alkylene,

[0024] X1 and X2 are identical or different and are amino, aminocarbonylor amidino,

[0025] Y1 and Y2 are imidazol-1-yl,

[0026] Z1 and Z2 are identical or different and are 5,2-pyridinylene,6-methyl-5,2-pyridinylene, 4,1-piperidin-ylene, 3,6-indazolylene,3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or1,4-cyclohexylene,

[0027] and where on the direct route between the terminal nitrogen atoms20 to 35, preferably 24 to 29, bonds have to be present,

[0028] and the salts of these compounds and the N-oxides of thenitrogen-containing heteroaryls, heteroarylenes and heterocycloalkylenesand their salts, where all those compounds are excluded in which one ormore of the variables B3, B4, B5 and B6 can have the meaning of a bond,resulting In the direct linkage of two heteroatoms.

[0029] 1-4C-Alkylene represents straight-chain or, branched1-4C-alkylene radicals, for example the methylene [—CH₂—], ethylene[—CH₂—CH₂—], trimethylene [—CH₂—CH₂—CH₂—], tetramethylene[—CH₂—CH₂—CH₂—CH₂—], 1,2-dimethylethylene [—CH(CH₃)—CH(CH₃)—],1,1-dimethylethylene [—C(CH₃)₂—CH₂—], 2,2-dimethylethylene[—CH₂—C(CH₃)₂—], Isopropylidene [—C(CH₃)₂—] or the 1-methylethylene[—CH(CH₃)—CH₂—] radical.

[0030] 14C-Alkyl represents straight-chain or branched alkyl radicalshaving 1 to 4 carbon atoms. Examples which may be mentioned are thebutyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and themethyl radical.

[0031] Hydroxy-1-4C-alkyl represents one of the 1-4C-alkyl radicalsmentioned above which is additionally substituted by a hydroxyl group.An example which may be mentioned is the hydroxymethyl radical.

[0032] 1-4C-Alkoxy represents radicals which, in addition to the oxygenatom, contain a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and, preferably, the ethoxyand methoxy radical.

[0033] 1-4C-Alkoxycarbonyl represents a carbonyl group to which one ofthe 1-4C-alkoxy radicals mentioned above is attached. Examples which maybe mentioned are the methoxycarbonyl [CH₃O—C(O)—] and the ethoxycarbonyl[CH₃CH₂O—C(O)—] radical.

[0034] 1-4C-Alkylcarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the 1-4C-alkyl radicals mentioned above.An example which may be mentioned is the acetyl radical.

[0035] The definitions of M and R2 contain chemical formulae, such as,for example,

[0036] Here, unilaterally unattached bonds, such as, for example, in the2-yl-malonic acid shown on the right mean that the substituent isattached in this position to the remainder of the molecule. The formulashown on the left indicates that the two radicals —CH₂—CH≡CH-D1- and-D2-CH≡CH—CH₂— and the radical(s) R1 can be attached to the benzene ringin any combination.

[0037] By definition, the groups Z1 and Z2 are located between groups B3and B5 (—B3-Z1-B5-) and B4 an B6 (—B4-Z2-B6-), respectively.Accordingly, in the divalent groupings mentioned by way of example (forexample 3,6-indolylene), the first number indicates the point ofattachment to the group B3 and B4, respectively, and the second numberindicates the point of attachment to the group B5 and B6, respectively.

[0038] The groups Z1 and Z2 can, inter alia, have the meaning1,4-cyclohexylene and 1,3-cyclohexylene. The invention embraces thecompounds of the formula I in which the groups B3, B5 and B4, B6,respectively, are attached (1e,4e), (1a,4a), (1e,4a), (1a,4e), (1e,3e),(1a,3a), (1e,3a), and (1a,3e) to the cyclohexylene radical. In thiscontext, particular preference is given to the (1e,4e) attachment (“e”means equatorial and “a” means axial).

[0039] In the context of this application, the term “terminal nitrogenatom” means in each case a nitrogen atom In the groups designated X1,X2, Y1 and Y2.

[0040] If the group X1 or X2 contains only one nitrogen atom, thisnitrogen atom is the terminal nitrogen atom.

[0041] If the group X1 or X2 contains a plurality of nitrogen atoms, thenitrogen atom which is furthest from the atom by means of which the bondto the group B3 (B5) or B4 (B6) is established is the terminal nitrogenatom.

[0042] If the group Y1 or Y2 contains only one ring nitrogen atom, thisring nitrogen atom is the terminal nitrogen atom.

[0043] If the group Y1 or Y2 contains a plurality of ring nitrogenatoms, the ring nitrogen atom which is furthest from the atom by meansof which the bond to the group B3 or B4 is established is the terminalnitrogen atom.

[0044] According to the invention, the direct route between the nitrogenatoms which act as terminal nitrogen atoms in the groups defined as X1(Y1) or X2 (Y2) Is considered to be the number of bonds which isobtained by counting the bonds which represent the shortest possibleconnection between the terminal nitrogen atoms.

[0045] The following example is meant to illustrate the determination ofthe number of bonds on the direct route between two terminal nitrogenatoms:

[0046] Here, the direct route comprises 27 bonds.

[0047] Preference is given to compounds of the formula I having amolecular weight below 600 g/mol.

[0048] Suitable salts for compounds of the formula I are—depending onthe substitution—all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically acceptable saltsof inorganic and organic acids customarily used in pharmacy. Thosesuitable are water-soluble and water-insoluble acid addition salts withacids such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyricacid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearicacid, toluenesulfonic acid, methanesulfonic acid or3-hydroxy-2-naphthoic acid, where the salts are employed in saltpreparation—depending on whether it Is concerned with a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

[0049] On the other hand, salts with bases are also suitable. Examplesof salts with bases which may be mentioned are alkali metal (lithium,sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

[0050] Pharmacologically unacceptable salts which can be obtainedinitially as process products, for example in the preparation of thecompounds according to the invention on an industrial scale, areconverted into pharmacologically acceptable salts by processes known tothe person skilled in the art.

[0051] It is known to the person skilled in the art that the compoundsaccording to the invention, and also their salts, may contain varyingamounts of solvents, for example when they are isolated in crystallineform. The Invention therefore also embraces all solvates and inparticular all hydrates of the compounds of the formula I, and also allsolvates and in particular all hydrates of the salts of the compounds ofthe formula I.

[0052] Compounds of the formula I which are to be emphasized are thosein which

[0053] M is a central building block selected from the group below

[0054] where

[0055] R1 is carboxyl, 1-4C-alkoxycarbonyl or hydroxy-1-4C-alkyl,

[0056] R2 is selected from the group consisting of

[0057] in which R21 is 1-4C-alkyl,

[0058] D1 is a bond or —CH₂—O—,

[0059] D2 is a bond or —O—CH₂— and

[0060] n is 1 or2,

[0061] A1 is —O—B1-A3-, -A5-B1-O—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—,—NH—C(O)—NH— or —O—C(O)—O—,

[0062] A2 is —O—B2-A4-, -A6-B2-O—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—,—NH—C(O)—NH— or —O—C(O)—O—,

[0063] A3 and A4 are identical or different and are —C(O)—NH—,—NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0064] A5 and A6 are identical or different and are —NH—C(O)—,—O—C(O)—NH—, —NH—C(O—O—, —NH—C(O)—NH— or —O—C(O)—O—,

[0065] B1 and B2 are identical or different and are 1-2C-alkylene,

[0066] K1 is —B3-Z1-B5-X1,

[0067] K2 is —B4-Z2-B6-X2,

[0068] B3 and B4 are identical or different and are a bond or1-2C-alkylene,

[0069] B5 and B6 are identical or different and are a bond or1-2C-alkylene,

[0070] X1 and X2 are identical or different and are amino or amidino,

[0071] Z1 and Z2 are identical or different and are 1,3-phenylene,1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,

[0072] and where on the direct route between the terminal nitrogen atoms20 to 35, preferably 24 to 29, bonds have to be present,

[0073] and the salts of these compounds, the N-oxides of the pyridinesand their salts.

[0074] Compounds of the formula I which are to be particularlyemphasized are those in which

[0075] M is a central building block selected from the group below

[0076] where

[0077] R1 is carboxyl, methoxycarbonyl, ethoxycarbonyl or hydroxymethyl,

[0078] n is 1 or 2,

[0079] A1 is —O—C(O)—NH—,

[0080] A2 is —O—C(O)—NH—,

[0081] K1 is —B3-Z1-B5-X1,

[0082] K2 is —B4-Z2-B6-X2,

[0083] B3 and B4 are identical and are methylene,

[0084] B5 and B6 are identical and are methylene,

[0085] X1 and X2 are identical and are amino,

[0086] Z1 and Z2 are identical or different and are 1,3-phenylene or1,4-phenylene,

[0087] and the salts of these compounds.

[0088] Preferred compounds of the formula I are

[0089] 3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-hydroxymethylbenzene;

[0090] methyl3,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;

[0091]3,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid;

[0092] methyl3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;

[0093]3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid;

[0094] methyl2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;

[0095]2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid,

[0096] dimethyl2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]terephthalate;

[0097] diethyl2,5-bis-[4-(3-aminomethylbenzylaminocarbonyloxy)but-2-ynyl-1-oxy]terephtlalate;

[0098] and the salts of these compounds.

[0099] The compounds of the formula I are constructed from a largenumber of building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4,B5, B6, K1, K2, X1, X2, Y1, Y2, Z1 a synthesized starting with any ofthese building blocks. If the compounds of the formula I are constructedlargely symmetrically, it is favorable to start the synthesis with thecentral building block M, whereas in the case of predominantlyasymmetrical compounds of the formula I the synthesis starting with oneof the end groups K1 or K2 may be advantageous.

[0100] Suitable starting materials for synthesizing the compounds of theformula I according to the invention are, for example,2,6-dibromoisonicotinic acid, 2,6-dibromonicotinic acid,2,4-dibromobenzoic acid, 3,5-dibromobenzoic acid,2,5-dibromoterephthalic acid, 2-(3,5-dibromophenyl)malonic acid, thecorresponding 1-4C-alkyl esters, (3,5-dibromophenyl)methanol and diethyl2,5-dihydroxyterephthalate.

[0101] Here, the building blocks are always linked using the samepattern, known per se to the person skilled in the art.

[0102] It is known to the person skilled In the art that the compoundsof the formula I can either be synthesized building block by buildingblock, or by initially constructing relatively large fragmentsconsisting of several individual building blocks, which can then bejoined to give the complete molecule.

[0103] Owing to the meanings which the individual building blocks of thecompounds of the formula I can assume, ether [—O—], keto [—C(O)—], amide[—C(O)—NH—, —NH—C(O)—], carbamate [—NH—C(O)O—, —O—C(O)NH—], carbamide[—NH—C(O)—NH—] or carbonate [—O—C(O)—O—] bridges are present in thecompounds of the formula I.

[0104] How to prepare such bridges is known per se to the person skilledin the art; suitable methods and starting materials for theirpreparation are described, for example, in March, Advanced OrganicChemistry, Reactions, Mechanisms and Structure, Third Edition, 1985,John Wiley & Sons.

[0105] Ether bridges can be prepared, for example, by the method ofWilliamson.

[0106] Keto bridges can be introduced, for example, as a component ofrelatively large building blocks, such as, for example, carboxylic acidderivatives.

[0107] There is also a large number of known methods for preparing amidebridges. An example which may be mentioned here is the reaction of acylchlorides with primary or secondary amines. Furthermore, reference isalso made to all the methods which have been developed for peptidechemistry.

[0108] Carbamate bridges can be prepared, for example, by reactingchloroformates with amines. The chloroformates for their part can besynthesized from alcohols and phosgene. A further variant forconstructing carbamate bridges is the addition of alcohols toisocyanates. Similarly to carbamate bridges, it is possible to preparecarbonate bridges starting from chloroformates, by reaction withalcohols (instead of amines).

[0109] Carbamide bridges can be prepared, for example, by reactingisocyanates with amines.

[0110] The preparation of compounds of the formula I may be shown in anexemplary manner using the reaction schemes 1, 2 and 3 below. Furthercompounds of the formula I can be prepared analogously, or by using theabovementioned methods known per se to the person skilled in the art.

[0111] It is also possible to convert compounds of the formula I byderivatization into further compounds of the formula I. Thus, forexample, compounds of the formula I having a nitrogen-containingheteroaryl, heteroarylene or heterocycloalkylene building block can beconverted by oxidation into the corresponding N-oxides.

[0112] The N-oxidation is carried out in a manner which Is likewiseknown to the person skilled in the art, for example using hydrogenperoxide in methanol or m-chloroperoxybenzoic acid in dichloromethane atroom temperature. Which reaction conditions are required In a particularcase for carrying out the process is known to the person skilled in theart owing to his expert knowledge.

[0113] It is furthermore known to the person skilled in the art that ifthere are a number of reactive centers on a starting material orintermediate, it may be necessary to block one or more reactive centerstemporarily by protective groups in order to allow a reaction to proceedspecifically at the desired reaction center. A detailed description ofthe use of a large number of proven protective groups is found, forexample, in T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

[0114] The isolation and purification of the substances according to theinvention is carried out in a manner known per se, for example bydistilling off the solvent under reduced pressure and recrystallizingthe resulting residue from a suitable solvent or subjecting it to one ofthe customary purification methods, such as, for example, columnchromatography on a suitable support material.

[0115] Salts are obtained by dissolving the free compound in a suitablesolvent (for example a ketone, such as acetone, methyl ethyl ketone ormethyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuranor dioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low-molecular-weight aliphatic alcohol, such as ethanolor isopropanol) which contains the desired acid or base, or to which thedesired acid or base Is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically unacceptablesalts can be converted into pharmacologically acceptable salts.

[0116] The examples below serve to illustrate the Invention In moredetail without restricting it. Likewise, further compounds of theformula 1, whose preparation is not explicitly described, can beprepared in an analogous manner or in a manner familiar per se to theperson skilled in the art using customary process techniques.

[0117] In the examples below, the abbreviation RT stands for roomtemperature, calc. for calculated and MS for mass spectrometry. Thecompounds mentioned by way of example and their salts are the preferredsubject of the invention.

EXAMPLES End Products General Procedure

[0118] A solution of the Boc- and/or tert-butyl-ester-protected divalentcompound (A4, A9-A14, A17 and A20; 1.0 mmol) in dioxane (21 ml) isadmixed with a saturated solution of HCI in dioxane (21 ml) and stirredat RT for 1-8 h. The reaction mixture is then diluted with diethyl ether(10 ml) and the resulting precipitate is filtered off and washed withdiethyl ether (3×5 ml). Drying under reduced pressure gives the titlecompounds (end products 1-9) as colorless solids.

1.3,5-Bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-hydroxymethyl-benzenedihydrochloride

[0119]

[0120] MS: calc.: C₅₁H₅₂N₄O₉ (540.8), found: [MH⁺] 541.3

2. Methyl3,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoatedihydrochloride

[0121]

[0122] MS: calc.: C₅₁H₅₂N₄O₉ (568.8), found: [MH⁺] 569.2

3. 3,5-Bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid dihydrochloride

[0123]

[0124] MS: calc.: C₅₁H₅₂N₄O₉ (554.6), found: [MH⁺] 555.2

4. Methyl3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoatedihydrochloride

[0125]

[0126] MS: calc.: C₅₁H₅₂N₄O₉ (568.8), found: [MH⁺] 569.2

5. 3,5-Bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid dihydrochloride

[0127]

[0128] MS: calc.: C₅₁H₅₂N₄O₉ (554.6), found: [MH⁺] 555.1

6. Methyl2,5-bis-13-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoatedihydrochloride

[0129]

[0130] MS: calc.: C₅₁H₅₂N₄O₉ (568.8), found: [MH⁺] 569.1

7. 2,5-Bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid dihydrochloride

[0131]

[0132] MS: calc.: C₅₁H₅₂N₄O₉ (554.6), found: [MH⁺] 555.1

8. Dimethyl2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]terephthalatedihydrochloride

[0133]

[0134] MS: calc.: C₃₄H₃₄N₄O₉ (626.7), found: [MH⁺] 627.2

9. Diethyl2,5-bis-[4-(3-aminomethylbenzylaminocarbonyloxy)but-2-ynyl-1-oxy]terephthalatedihydrochloride

[0135]

[0136] MS: calc.: C₃₈H₄₂N₄O₁₀ (714.8), found: [MH⁺] 715.2

Starting Materials A1. tert-Butyl-(3,5-dibromobenzyloxy)diphenylsilane

[0137] With stirring, imidazole (1.1 g, 16.0 mmol) Is added to asolution of 3,5-dibromobenzyl alcohol (2.8 g, 10.5 mmol) in absolute DMF(20 ml), and the mixture is cooled to 0° C. tert-Butyidiphenylsilylchloride (3.3 ml, 17.8 mmol) is added dropwise to the reaction solution,which is then stirred at 0° C. for 2 h. The mixture is then warmed to RTand stirred for another 2 h. The reaction mixture is diluted with ethylacetate (20 ml) and extracted with a semisaturated aqueous NH₄Clsolution (20 ml). The organic phase is dried over MgSO₄, filtered offand concentrated under reduced pressure. Further purification is carriedout by chromatography [PE/EA (99:1)] on a silica gel column. This givesthe title compound (5.0 g) as a colorless solid. TLC, silica gel (glassplates), [petroleum ether/ethyl acetate (99:1)], R_(f)=0.8.

A2.3,5-Bis-[(3-hydroxyprop-1-ynyl)]-1-(tert-butyldiphenylsilanyloxymethyl)benzene

[0138] Pd(Ph₃P)₄ (520 mg), CuBrSMe₂ (200 mg) and propargyl alcohol (3.08ml, 35.1 mmol) are added successively to a solution oftert-butyl-(3,5-dibrombenzyloxy)diphenylsilane (A1, 5.0 g, 9.9 mmol) intriethylamine (50 ml), and the mixture is stirred at RT for 10 min andthen under reflux at 80° C. for 2.5 h. After cooling, the reactionmixture is filtered off with suction through kieselguhr, and the filtercake is washed with ethyl acetate (20 ml). The organic phase Isconcentrated under reduced pressure. Further purification is carried outby chromatography [toluene/acetone (8:2)] on a silica gel column. Thisgives the title compound (4.0 g) as a colorless solid. TLC, silica gel(glass plates), [toluenelacetone (8:2)], R_(f)=0.48.

[0139] MS: calc.: C₂₉H₃₀O₃Si (454.6), found: [MNH₄ ⁺] 472.1

A3.3,5-Bis-[3-(4-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-(tert-butyidiphenyisilyloxymethyl)benzene

[0140] N,N-Carbonyldiimidazole (4.81 g, 37.7 mmol) is added to asolution of3,5-bis-[(3-hydroxyprop-1-ynyl)]-1-(tert-butyldiphenylsilanyloxymethyl)benzene(A2, 3.9 g, 8.6 mmol) in absolute CH₂Cl₂ (78 ml), and the mixture isstirred at RT for 2 h. The reaction solution is diluted with CH₂Cl₂ (80ml) and extracted with a semisaturated aqueous NaCl solution (150 ml).The organic phase is dried over MgSO₄, filtered off and concentratedunder reduced pressure. The resulting residue is taken up in absoluteCH₂Cl₂ (78 ml), 4-(tert-butyloxycarbonylaminomethyl)benzylamine (4.81 g,20.4 mmol) is added and the mixture is stirred at RT overnight. Diethylether (80 ml) is added to the reaction solution and the resultingprecipitate is filtered off, washed with diethyl ether (80 ml) anddried. This gives the title compound (6.35 g) as a colorless solid. TLC,silica gel (glass plates), [toluene/acetone (7.5:2.5)], R_(f)=0.75.

[0141] MS: calc.: C₅₇H₆₆N₄O₉Si (978.0), found: [MNH₄ ⁺] 996.1; [MNa⁺]1001.2

A4.3,5-Bis-[3-(4-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-hydroxymethylbenzene

[0142] A 1M solution of tetrabutylammonium fluoride in THF (2.3 ml, 2.3mmol) is added to a suspension of3,5-bis-[3-(4-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-(tert-butyl-diphenylsilyloxymethyl)benzene(A3, 2.0 g, 2.04 mmol) in absolute THF (16 ml), and the mixture isstirred at RT for 20 min. The reaction solution is then diluted withethyl acetate (16 ml) and extracted with a semisaturated aqueous NH₄Clsolution (20 ml). The organic phase is dried over MgSO₄, filtered offand concentrated under reduced pressure. The resulting residue is takenup in CH₂Cl₂ (10 ml) and crystallized with petroleum ether. This givesthe title compound (1.3 g) as a colorless solid. TLC, silica gel (glassplates), [toluene/acetone] (7.5:2.5)], R_(f)=0.31.

[0143] MS: calc.: C₄₁H₄₈N₄O₉ (740.8), found: [MH⁺]740.9, [MNH₄ ⁺] 758.0;[MNa⁺] 763.2

A5. Methyl 2,5-bis-(3-hydroxyprop-1-ynyl)benzoate

[0144] Pd(Ph₃P)₄ (1.95 g), CuBrSMe₂ (0.75 g) and propargyl alcohol (5.35ml, 70.0 mmol) are added successively to a solution of methyl2,5-dibromobenzoate (10.0 g, 34.0 mmol) in triethylamine (235 ml), andthe mixture is stirred at RT for 10 min and then -under reflux at 80° C.for 3 h. After cooling, the reaction mixture is filtered off withsuction through kieselguhr, and the filter cake is washed with ethylacetate (50 ml). The organic phase is concentrated under reducedpressure. Further purification is carried out by chromatography[toluene/acetone (8:2)] on a silica gel column. This gives the titlecompound (6.0 g) as a colorless solid. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.16.

[0145] MS: calc.: C₁₄H₁₂O₄ (244.2), found: [MH⁺] 245.1, [MNH₄ ⁺] 262.1

A6. tert-Butyl 3,5-dibromobenzoate

[0146] EDC (14.0 g, 73.0 mmol) and DMAP (4.0 g) are added to a solutionof 3,5-dibromobenzoic acid (10.0 g, 36.0 mmol) and tert-butanol (3.4 g,46.8 mmol) in absolute CH₂Cl₂ (100 ml) and absolute pyridine (30 ml),and the mixture is stirred at RT for 1 h and then at 50° C. for 2 h. Thereaction solution is diluted with CH₂Cl₂ (100 ml) and extracted with asemisaturated aqueous NH₄Cl solution (200 ml) (2×), dried over MgSO₄,filtered off and concentrated under reduced pressure. Furtherpurification by chromatography [toluene/acetone (95:5)] on a silica gelcolumn gives the title compound (7.7 g) as slightly yellow crystals.TLC, silica gel, glass plates, [toluene/acetone (7.5:2.5)], R_(f)=0.78.

[0147] MS: calc.: C₁₁H₁₂Br₂O₂ (336.0), found: [M⁺] 336.0

A7. tert-Butyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate

[0148] Pd(Ph₃P)₄ (1.08 g), CuBrSMe₂ (0.41 g) and propargyl alcohol (2.95g, 50.2 mmol) are added successively to a solution of tert-butyl3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml),and the mixture is stirred at RT for 10 min and then under reflux at 80°C. for 3.5 h. After cooling, the reaction mixture is filtered off withsuction through kieselguhr, and the filter cake is washed with ethylacetate (50 ml). The organic phase is concentrated under reducedpressure. Further purification is carried out by chromatography[toluene/acetone (8:2)] on a silica gel column. This gives the titlecompound (5.7 9) as a colorless solid. TLC, silica gel (glass plates),[toluene/acetone (7.5:2.5)], R_(f)=0.15.

[0149] MS: calc.: C₁₇H₁₈O₄ (286.3), found: [MNH₄ ⁺] 304.4

A8. Methyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate

[0150] Pd(Ph₃P)₄ (1.08 g), CuBrSMe₂ (0.41 g) and propargyl alcohol (2.95g, 50.2 mmol) are added successively to a solution of methyl3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml),and the mixture is stirred at RT for 10 min and then under reflux at 80°C. for 3.5 h. After cooling, the reaction mixture is filtered off withsuction through kieselguhr, and the filter cake is washed with ethylacetate (50 ml). The organic phase is concentrated under reducedpressure. Further purification is carried out by chromatography[toluene/acetone (8:2)] on a silica gel column. This gives the titlecompound (5.7 g) as a colorless solid. TLC, silica gel (glass plates),[toluene/acetone (7.5:2.5)], R_(f)=0.15.

[0151] MS: calc.: C₁₄H₁₂O₄ (244.2), found: [MH⁺] 245.0, [MNH₄ ⁺] 262.3

A9. tert-Butyl3,5-bis-[3-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate

[0152] N,N-Carbonyldiimidazole (0.98 g, 4.0 mmol) is added to a solutionof tert-butyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate (A7, 0.5 g, 1.80mmol) in absolute CH₂Cl₂ (12 ml), and the mixture is stirred at RT for 2h. The reaction solution is diluted with CH₂Cl₂ (12 ml) and extractedwith a semisaturated aqueous NaCl solution (20 ml). The organic phase isdried over MgSO₄, filtered off and concentrated under reduced pressure.The resulting residue is taken up in absolute CH₂Cl₂ (12 ml),3-(tert-butyloxy-carbonylaminomethyl)benzylamine (0.95 g, 4.0 mmol) isadded and the mixture is stirred at RT overnight. The reaction solutionis then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (20 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(85:15)] on a silica gel column. This gives the title compound (0.65 g)as a colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.41.

[0153] MS: calc.: C₄₅H₅₄N₄O₁₀ (810.0), found: [MH⁺] 811.0, [MNH₄ ⁺]828.0, [MNa⁺] 833.3

A10. tert-Butyl3,5-bis-[3-(4-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyioxy)prop-1-ynyl]benzoate

[0154] N,N-Carbonyidiimidazole (0.98 g, 4.0 mmol) is added to a solutionof tert-butyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate (A7, 0.5 g, 1.80mmol) in absolute CH₂Cl₂ (12 ml), and the mixture is stirred at RT for 2h. The reaction solution is diluted with CH₂Cl₂ (12 ml) and extractedwith a semisaturated aqueous NaCl solution (20 ml). The organic phase isdried over MgSO₄, filtered off and concentrated under reduced pressure.The resulting residue is taken up in absolute CH₂Cl₂ (12 ml),4-(tert-butyloxy-carbonylaminomethyl)benzylamine (0.95 g, 4.0 mmol) isadded and the mixture is stirred at RT overnight. The reaction solutionis then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (20 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [CH₂Cl₂/MeOH(99:1)] on a silica gel column. This gives the title compound (0.8 g) asa colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.40.

[0155] MS: calc.: C₄₅H₅₄N₄O₁₀ (810.0), found:.[MH⁺]810.5, [MNH₄ ⁺]827.9, [MNa⁺] 833.3

A11. Methyl2,5-bis-[3-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate

[0156] N,N-Carbonyldiimidazole (1.05 g, 4.26 mmol) is added to asolution of methyl 2,5-bis-(3-hydroxyprop-1-ynyl)benzoate (A5, 0.52 g,2.13 mmol) in absolute CH₂Cl₂ (12 ml), and the mixture is stirred at RTfor 2 h. The reaction solution is diluted with CH₂Cl₂ (12 ml) andextracted with a semisaturated aqueous NaCl solution (20 ml). Theorganic phase is dried over MgSO₄, filtered off and concentrated underreduced pressure. The resulting residue is taken up in absolute CH₂Cl₂(12 ml), 3-(tert-butyloxy-carbonylaminomethyl)benzylamine (1.01 g, 4.26mmol) is added and the mixture is stirred at RT overnight. The reactionsolution is then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (20 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(8:2)] on a silica gel column. This gives the title compound (0.6 g) asa colorless amorphous residue, TLC, silica gel (glass plates),[toluene/acetone (7.5:2.5)], R_(f)=0.33.

[0157] MS: calc.: C₄₂H₄₈N₄O₁₀ (768.8), found: [MNa⁺] 791.1

A12.2,5-Bis-[3-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid

[0158] A 5N aqueous NaOH solution (1 ml) is added dropwise to asuspension of methyl2,5-bis-[3-(3-N-tertbutoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate(A11, 0.45 g, 0.58 mmol) in ethanol (3 ml), and the mixture is stirredat RT for 1 h. Using a 20% strength aqueous KHSO₃ solution, the reactionmixture is adjusted to pH 3 and extracted with CH₂Cl₂ (50 ml). Theorganic phase is then dried over MgSO₄, filtered off and concentratedunder reduced pressure. Further purification is carried out bychromatography [CH₂Cl₂/MeOH (95:5)] on a silica gel column. This givesthe title compound (0.15 g) as a colorless solid. TLC, silica gel (glassplates), [CH₂Cl/MeOH (95:5)], R_(f)=0.44.

[0159] MS: calc.: C₄₁H₄₆N₄O₁₀ (754.6), found: [MH⁺] 754.8, [MNa⁺] 777.2

A13. Methyl3,5-bis-[3-(4-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate

[0160] N,N-Carbonyldiimidazole (0.98 g, 4.0 mmol) is added to a solutionof methyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate (A8, 0.5 g, 1.80 mmol)in absolute CH₂Cl₂ (12 ml), and the mixture is stirred at RT for 2 h.The reaction solution is diluted with CH₂Cl₂ (12 ml) and extracted witha semisaturated aqueous NaCl solution (20 ml). The organic phase isdried over MgSO₄, filtered off and concentrated under reduced pressure.The resulting residue is taken up in absolute CH₂Cl₂ (12 ml),4-(tert-butyloxy-carbonylaminomethyl)benzylamine (0.95 g, 4.0 mmol) isadded and the mixture is stirred at RT overnight. The reaction solutionis then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (20 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(85:15)] on a silica gel column. This gives the title compound (1.1 g)as a colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.44.

[0161] MS: calc.: C₄₂H₄₈N₄O₁₀ (768.8), found: [MNa⁺] 791.2

A14. Methyl3,5-bis-[3-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate

[0162] N,N-Carbonyldiimidazole (0.98 9, 4.0 mmol) is added to a solutionof methyl 3,5-bis-(3-hydroxyprop-1-ynyl)benzoate (A8, 0.5 g, 1.80 mmol)In absolute CH₂Cl₂ (12 ml), and the mixture is stirred at RT for 2 h.The reaction solution is diluted with CH₂Cl₂ (12 ml) and extracted witha semisaturated aqueous NaCl solution (20 ml). The organic phase isdried over MgSO₄, filtered off and concentrated under reduced pressure.The resulting residue is taken up in absolute CH₂Cl₂ (12 ml),3-(tert-butyloxy-carbonylaminomethyl)benzylamine (0.95 9, 4.0 mmol) isadded and the mixture is stirred at RT overnight. The reaction solutionis then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (20 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(85:15)] on a silica gel column. This gives the title compound (1.1 g)as a colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.43.

[0163] MS: calc.: C₄₂H₄₈N₄O₁₀ (768.8), found: [MNa⁺] 791.3

A15. Dimethyl 3,5-dibromoterephthalate

[0164] Concentrated H₂SO₄ (15 ml) is added dropwise to a solution of2,5-dibromoterephthalic acid (5.0 g, 15.44 mmol) in absolute methanol(75 ml), and the mixture is stirred under reflux for 4 h. The resultingprecipitate is filtered off from the reaction mixture and Washed with alittle methanol (15 ml). This gives the title compound (4.85 g) as acolorless solid. TLC, silica gel (glass plates), [toluene/acetone(8:2)], R_(f)=0.75.

A16. Dimethyl 3,5-bis-(3-hydroxyprop-1-ynyl)terephthalate

[0165] Pd(Ph₃P)₄ (0.27 g), CuBrSMe₂ (0.11 g) and propargyl alcohol (0.72g, 12.9 mmol) are added successively to a solution of dimethyl3,5-dibromoterephthalate (Al 5, 2.0 g, 5.7 mmol) in triethylamine (40ml), and the mixture is stirred at RT for 10 min and then under refluxat 80° C. for 3.5 h. After cooling, the reaction mixture is filtered offwith suction through kieselguhr and washed with ethyl acetate (20 ml).The organic phase is concentrated under reduced pressure. Furtherpurification is carried out by chromatography [toluene/acetone (8:2)] ona silica gel column. This gives the title compound (1.4 g) as acolorless solid. TLC, silica gel (glass plates), (toluene/acetone(8:2)], R_(f)=0.20.

[0166] MS: calc.: C₁₆H₁₄O₆ (302.9), found: [MNH₄ ⁺] 320.1

A17. Dimethyl2,5-bis-[3-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)prop-1-ynyl]terephthalate

[0167] N,N-Carbonyldiimidazole (0.31 g, 1.9 mmol) is added to a solutionof dimethyl 3,5-bis-(3-hydroxyprop-1-ynyl)terephthalate (A16, 0.2 g,0.66 mmol) in absolute CH₂Cl₂ (5 ml), and the mixture is stirred at RTfor 2 h. The reaction solution is diluted with CH₂Cl₂ (5 ml) andextracted with a semisaturated aqueous NaCl solution (10 ml). Theorganic phase is dried over MgSO4, filtered off and concentrated underreduced pressure. The resulting residue is taken up in absolute CH₂Cl₂(5 ml), 3-(tert-butyloxy-carbonylaminomethyl)benzylamine (0.34 g, 1.45mmol) is added and the mixture is stirred at RT overnight. The reactionsolution is then diluted with ethyl acetate (10 ml) and extracted with asemisaturated aqueous NH₄Cl solution (10 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(8:2)] on a silica gel column. This gives the title compound (0.16 g) asa colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (8:2)], R_(f)=0.31.

[0168] MS: calc.: C₄₄H₅₀N₄O₁₂ (826.9), found: [MNH₄ ⁺] 844.0, [MNa⁺]849.3

A18. (4-Hydroxy-but-2-ynyl)toluene-4-sulfonate

[0169] At 10° C., a solution of triethylamine (17.5 ml, 128.0 mmol) inabsolute dioxane (60 ml) is added dropwise to a solution ofbut-2-yne-1,4-diol (10 g, 116.1 mmol) and 4-toluenesulfonyl chloride(24.4 g, 128.0 mmol) in absolute dioxane (230 ml), and the mixture isstirred for 2 h. The mixture is then stirred at RT overnight. Thereaction mixture is filtered off with suction through kieselguhr, andthe filter cake is washed with ethyl acetate (20 ml). The organic phaseis concentrated under reduced pressure. Further purification is carriedout by chromatography [toluene/acetone (8.5:1.5)] on a silica gelcolumn. This gives the title compound (7.5 g) as a light yellow oil.TLC, silica gel (glass plates), [toluene/acetone (8:2)], R_(f)=0.49.

[0170] MS: calc.: C₁₁H₁₂O₄S (240.3), found: [MNH₄ ⁺] 258.0

A19. Diethyl 2,5-bis-(4-hydroxy-but-2-ynyl-1-oxy)terephthalate

[0171] Finely powdered K₂CO₃ (0.7 g) is added to a solution of diethyl2,5-dihydroxyterephthalate (0.4 g, 1.6 mmol) and(4-hydroxy-but-2-ynyl)toluene4-sulfonate (A18, 0.8 g, 3.33 mmol) inabsolute acetone (25 ml), and the mixture is stirred under reflux for 18h. After cooling, the reaction mixture is filtered off with suctionthrough kieselguhr, and the filter cake is washed with ethyl acetate (20ml). The organic phase is concentrated under reduced pressure. Furtherpurification is carried out by chromatography [toluene/acetone (8:2)] ona silica gel column. This gives the title compound (0.44 g) as a lightyellow oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)],R_(f)=0.26.

[0172] MS: calc.: C₁₈H₁₈O₈ (390.3), found: [MH⁺] 391.1, [MNH₄ ⁺] 408.0

A20. Diethyl2,5-bis-[4-(3-N-tert-butoxycarbonylaminomethylbenzylaminocarbonyloxy)but-2-ynyl-1-oxy]terephthalate

[0173] N,N-Carbonyldiimidazole (1.6 g, 6.2 mmol) is added to a solutionof diethyl 2,5-bis-(4-hydroxy-but-2-ynyl-1-oxy)terephthalate (A19, 0.3g, 0.78 mmol) In absolute CH₂Cl₂ (15 ml), and the mixture is stirred atRT for 2 h. The reaction solution is diluted with CH₂Cl₂ (15 ml) andextracted with a semisaturated aqueous NaCl solution (20 ml). Theorganic phase is dried over MgSO₄, filtered off and concentrated underreduced pressure. The resulting residue is taken up in absolute CH₂Cl₂(15 ml), 3-(tert-butyloxycarbonylaminomethyl)benzylamine (0.41 g, 1.73mmol) is added and the mixture is stirred at RT overnight. The reactionsolution is then diluted with ethyl acetate (15 ml) and extracted with asemisaturated aqueous NH₄Cl solution (15 ml). The organic phase is driedover MgSO₄, filtered off and concentrated under reduced pressure.Further purification is carried out by chromatography [toluene/acetone(8:2)] on a silica gel column. This gives the title compound (0.42 g) asa colorless amorphous residue. TLC, silica gel (glass plates),[toluene/acetone (7.5:2.5)], R_(f)=0.56.

[0174] MS: calc.: C₄₈H₅₈N₄O₁₄ (914.0), found: [MH⁺] 914.8, [MNH₄ ⁺]931.9, [MNa⁺] 937.3

Commercial Utility

[0175] As tryptase Inhibitors, the compounds according to the inventionhave useful pharmacological properties which make them commerciallyutilizable. Human tryptase is a serin protease which is the main proteinin human mast cells. Tryptase comprises eight closely related enzymes(α1, α2, β1a, β1b, β2, β3, mMCP-7-like-1, mMCP-7-like-2; 85 to 99%sequence identity) (cf. Miller et al., J. Clin. Invest. 84 (1989)1188-1195; Miller et al., J. Clin. Invest. 86 (1990) 864-870;Vanderslice et al., Proc. Natl. Acad. Sci., USA 87 (1990) 3811-3815;Pallaoro et al., J. Biol. Chem. 274 (1999) 3355-3362). However, only theβ-tryptases (Schwartz et al., J. Clin. Invest. 96 (1995) 2702-2710;Sakai et al., J. Clin. Invest. 97 (1996) 988-995) are activatedintracellularly and stored in catalytically active form in secretorygranules. Compared with other known serin proteases, such as, forexample, trypsin or chymotrypsin, tryptase has some special properties(Schwartz et al., Methods Enzymol. 244, (1994), 88-100; G. H. Caughey,“Mast cell proteases in immunology and biology”. Marcel Dekker, Inc.,New York, 1995). Tryptase from human tissue has a noncovalently-linkedtetrameric structure which has to be stabilized by heparin or otherproteoglycanes to be proteolytically active. Together with otherinflammatory mediators, such as, for example, histamine andproteoglycanes, tryptase is released when human mast cells areactivated. Because of this, tryptase is thought to play a role in anumber of disorders, in particular in allergic and Inflammatorydisorders, firstly because of the importance of the mast cells in suchdisorders and secondly since an increased tryptase concentration wasobserved in a number of disorders of this type. Thus, tryptase isassociated, inter alia, with the following diseases: acute and chronic(in particular inflammatory and allergen-induced) airway disorders ofvarious origins (for example bronchitis, allergic bronchitis, bronchialasthma, COPD); interstitial lung disorders; disorders based on allergicreactions of the upper airways, (pharynx, nose) and the adjacent regions(for example paranasal sinuses, conjunctivae), such as, for example,allergic conjunctvitis and allergic rhinitis; disorders of the arthritistype (for example rheumatoid arthritis); autoimmune disorders, such asmultiple sclerosis; furthermore neurogenic inflammations,arteriosclerosis and cancer; moreover periodontitis, anaphylaxis,interstitial cystitis, dermatitis, psoriasis, sderodermia/systemicsclerosis, inflammatory intestinal disorders (Crohn's disease,inflammatory bowel disease) and others. In particular, tryptase seems tobe connected directly to the pathogenesis of asthma (Caughey, Am. J.Respir. Cell Mol. Biol. 16 (1997), 621-628; R. Tanaka, “The role oftryptase in allergic inflammation” in: Protease Inhibitors, IBC LibrarySeries, 1979, Chapter 3.3.1-3.3.23).

[0176] A further subject of the invention are the compounds according tothe invention for use In the treatment and/or prophylaxis of diseases,in particular the diseases mentioned.

[0177] The Invention likewise relates to the use of the compoundsaccording to the invention for preparing medicaments which are employedfor the treatment and/or prophylaxis of the diseases mentioned.

[0178] Medicaments for the treatment and/or prophylaxis of the diseasesmentioned, which contain one or more of the compounds according to theinvention, are furthermore a subject of the invention.

[0179] The medicaments are prepared by processes which are known per seand are familiar to the person skilled in the art. As medicaments, thecompounds according to the invention (=active compounds) are eitheremployed as such, or preferably in combination with suitablepharmaceutical excipients, for example in the form of tablets, coatedtablets, capsules, suppositories, patches, emulsions, suspensions, gelsor solutions, the active compound content advantageously being between0.1 and 95%.

[0180] The person skilled in the art is familiar, on the basis ofhis/her expert knowledge, with the excipients which are suitable for thedesired pharmaceutical formulations. In addition to solvents,gel-forming agents, ointment bases and other active compound vehicles,it is possible to use, for example, antioxidants, dispersants,emulsifiers, preservatives, solubilizers or permeation promoters.

[0181] For the treatment of diseases of the respiratory tract, thecompounds according to the invention are preferably also administered byinhalation, preferably in the form of an aerosol, with the aerosolparticles of solid, liquid or mixed composition having a diameter offrom 0.5 to 10 μm, advantageously of from 2 to 6μm.

[0182] The aerosol can be produced, for example, using pressure-drivennozzle nebulizers or ultrasonic nebulizers, advantageously, however,using propellant gas-driven metered aerosols or by means of thepropellant gas-free use of micronized active compounds from inhalationcapsules.

[0183] Depending on the inhalation system employed, the administrationforms also contain, in addition to the active compounds, the requisiteauxiliary substances, for example propellant gases (e.g. Frigen in thecase of metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, aromatizing agents, fillers (e.g. lactose inthe case of powder Inhalers) and, where appropriate, additional activecompounds.

[0184] For the purposes of Inhalation, there are available a largenumber of appliances which can be used to generate aerosols of optimalparticle size and administer them using an inhalabon technique which isas appropriate as possible for the patient. In addition to usingattachments (spacers and expanders) and pear-shaped containers (e.g.Nebulator® and Volumatic®), and also automatic spray puff releasers(Autohaler®) for metered aerosols, a number of technical solutions areavailable, particularly in the case of the powder Inhalers (e.g.Diskhaler®, Rotadisk®, Turbohaler® or the Inhaler described in Europeanpatent application 0 505 321), which technical solutions can be used toachieve optimal administration of the active compound.

[0185] For the treatment of dermatoses, the compounds according to theinvention are in particular used in the form of those medicaments whichare suitable for topical administration. For the preparation of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical excipientsand further processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

[0186] The medicaments according to the invention are prepared byprocesses known per se. The dosage of the active compounds in the caseof systemic therapy (p.o. or i.v.) is between 0.1 and 10 mg per kilogramper day.

Biological Investigations

[0187] The documented pathophysiological effects of mast cell tryptaseare caused directly by the enzymatic activity of the protease.Accordingly, they are reduced or blocked by inhibitors which inhibit theenzymatic activity of the tryptase. A suitable measure for the affinityof a reversible inhibitor to the target protease is the equilibriumdissociation constant K_(i) of the enzyme-inhibitor complex. This K₁value can be determined via the effect of the inhibitor on thetryptase-induced cleavage of a chromogenic peptide-p-nitroanilidesubstrate or a fluorogenic peptide-aminomethyicoumarin substrate.

Methodology

[0188] The dissociation constants for the tryptase-inhibitor complexesare determined under equilibrium conditions in accordance with thegeneral proposals of Bieth (Bieth J G, Pathophysiological Interpretationof kinetic constants of protease inhibitors, Bull. Europ. Physiopath.Resp. 16:183-195, 1980) and the methods of Sommerhoff et al. (SommerhoffC P et al., A Kazal-type inhibitor of human mast cell tryptase:isolation from the medical leech Hirudo medicinalis, characterization,and sequence analysis, Biol. Chem. Hoppe-Seyler 375: 685-694, 1994).

[0189] Human tryptase is isolated from lung tissue or preparedrecombinantly; the specific activity of the protease, determined bytitration, is usually greater than 85% of the theoretical value. In thepresence of heparin (0.1-50 μg/ml) for stabilizing the protease,constant amounts of the tryptase are incubated with increasing amountsof the inhibitors. After an equilibrium between the reaction partnershas formed, the remaining enzyme activity after addition of thepeptide-p-nitroanilide substrate tos-Gly-Pro-Arg-pNA is determined andthe cleavage of the latter is monitored at 405 nm for 3 min.Alternatively, the remaining enzymatic activity can also be determinedusing fluorogenic substrates. The apparent dissociation constantsK_(iapp) (i.e. in the presence of substrate) are subsequently determinedby adapting the enzyme rates to the general equation for reversibleinhibitors (Morrison J F, Kinetics of the reversible inhibition ofenzyme-catalysed reactions by tight-binding inhibitors, Biochim.Biophys. Acta 185, 269-286, 1969) using non-linear regression:

V ₁ /V ₀=1−{E _(t) +I _(t) +K _(iapp)−[(E _(t) +I _(t) +K _(iapp))²-4E_(t) I _(t)]^(1/2)}/2E _(t)

[0190] V₁ and V₀ are the rates in the presence and absence,respectively, of the inhibitor, and E_(t) and I_(t) are the tryptase andinhibitor concentrations, respectively.

[0191] The apparent dissociation constants determined for the compoundsaccording to the invention are shown in Table A below, where the numbersof the compounds correspond to the numbers of the compounds in theexamples. TABLE A Inhibition of human tryptase Compound K_(iapp) (μM) 10.014 2 0.0016 3 0.04 4 0.058 5 0.25 6 0.0003 7 0.0086 8 0.0023 9 0.006

1. A compound of the formula I

in which M is a central building block selected from the group below

where R1 is carboxyl, 1-4C-alkoxycarbonyl or hydroxy-1-4C-alkyl, R2 isselected from the group consisting of

in which R21 is 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl or14C-alkylcarbonyl, D1 is a bond or —CH₂—O—, D2 is a bond or —O—CH₂— andn is 1 or 2, A1 is —O—B1-A3-, -A5-B1-O—, —C(O)—, —C(O)—NH—, —NH—C(O)—,—O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—, A2 is —O—B2-A4-,-A6-B2-O—, —C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—,—NH—C(O)—NH— or —O—C(O)—O—, A3 and A4 are identical or different and are—C(O)—, —C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or—O—C(O)—O—, A5 and A6 are identical or different and are —C(O)—,—C(O)—NH—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or—O—C(O)—O—, B1 and B2 are identical or different and are 1-4C-alkylene,K1 is —B3-X1, —B3-Y1 or —B3-Z1-B5-X1, K2 is —B4-X2, —B4-Y2 or—B4-Z2-B6-X2, B3 and B4 are identical or different and are a bond or1-4C-alkylene, B5 and B6 are Identical or different and are a bond or1-2C-alkylene, X1 and X2 are identical or different and are amino,aminocarbonyl or amidino, Y1 and Y2 are imidazol-1-yl, Z1 and Z2 areidentical or different and are 5,2-pyridinylene,6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene,3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or1,4-cyclohexylene, and where on the direct route between the terminalnitrogen atoms 20 to 35 bonds have to be present, and the salts of thiscompound and the N-oxides of the nitrogen-containing. heteroaryls,heteroarylenes and heterocycloalkylenes and their salts, where all thosecompounds are excluded in which one or more of the variables B3, B4, B5and B6 can have the meaning of a bond, resulting in the direct linkageof two heteroatoms.
 2. A compound of the formula I as claimed in claim 1in which M is a central building block selected from the group below

where R1 is carboxyl, 1-4C-alkoxycarbonyl or hydroxy-1-4C-alkyl, R2 isselected from the group consisting of

in which R21 is 1-4C-alkyl, D1 is a bond or —CH₂—O—, D2 is a bond or—O—CH₂— and n is 1 or 2, A1 is —O—B1-A3-, -A5-B1-O—, —NH—C(O)—,—O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or —O—C(O)—O—, A2 is —O—B2-A4-,-A6-B2-O—, —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH— or—O—C(O)—O—, A3 and A4 are identical or different and are —C(O)—NH—,—NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)NH— or —O—C(O)—O, A5 and A6are identical or different and are —NH—C(O)—, —O—C(O)—NH—, —NH—C(O)—O—,—NH—C(O)—NH— or —O—C(O)—O—, B1 and B2 are identical or different and are1-2C-alkylene, K1 is —B3-Z1-B5-X1, K2 is —B4-Z2-B6-X2, B3 and B4 areidentical or different and are a bond or 1-2C-alkylene, B5 and B6 areidentical or different and are a bond or 1-2C-alkylene, X1 and X2 areidentical or different and are amino or amidino, Z1 and Z2 are identicalor different and are 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or1,4-cyclohexylene, and where on the direct route between the terminalnitrogen atoms 20 to 35 bonds have to be present, and the salts of thiscompound, the N-oxides of the pyridines and their salts.
 3. A compoundof the formula I as claimed in claim 1 in which M is a central buildingblock selected from the group below

where R1 is carboxyl, methoxycarbonyl, ethoxycarbonyl or hydroxymethyl,n is 1 or 2, A1 is —O—C(O)—NH—, A2 is —O—C(O)—NH—, K1 is —B3-Z1-B5-X1,K2 is —B4-Z2-B6-X2, B3 and B4 are identical and are methylene, B5 and B6are identical and are methylene, X1 and X2 are Identical and are amino,Z1 and Z2 are identical or different and are 1,3-phenylene or1,4-phenylene, and the salts of this compound.
 4. A compound of theformula I as claimed in claim 1 having the chemical name3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]-1-hydroxymethylbenzene;methyl3,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;3,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid; methyl3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;3,5-bis-[3-(4-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid; methyl2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoate;2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]benzoicacid; dimethyl2,5-bis-[3-(3-aminomethylbenzylaminocarbonyloxy)prop-1-ynyl]terephthalate;diethyl2,5-bis-[4-(3-aminomethylbenzylaminocarbonyloxy)but-2-ynyl-1-oxy]terephthalate;and the salts of this compound.
 5. A compound of the formula I asclaimed in claim 1 or 2, where on the direct route between the terminalnitrogen atoms 24 to 29 bonds are present.
 6. A compound of the formulaI as claimed in any of claims 1, 2 and 3 having a molecular weight ofbelow 600 g/mol.
 7. A medicament comprising one or more compounds of theformula I as claimed in claim 1 together with customary auxiliariesand/or excipients.
 8. A compound of the formula I as claimed in claim 1for treating diseases.
 9. The use of compounds of the formula I asclaimed in claim 1 for preparing medicaments for treating respiratorydisorders.